Chronic heart failure and heart transplantation: The relationship between autonomic function and cardiac performance

Abstract

Chronic heart failure (CHF) is a complex clinical syndrome characterized by impaired cardiac function and neurohormonal dysregulation. While CHF has traditionally been regarded as a hemodynamic disorder, growing evidence highlights the pivotal role of autonomic nervous system (ANS) dysfunction in its progression and prognosis. The ANS, comprising sympathetic and parasympathetic branches, exerts significant control over cardiac function, including heart rate, contractility, and vascular tone. In CHF, sympathetic overactivation coupled with parasympathetic withdrawal contributes to adverse cardiac remodeling, arrhythmogenesis, and further deterioration of cardiac performance. This minireview summarizes current knowledge on the role of autonomic dysfunction in CHF and heart transplantation. It focuses on how sympathetic nervous system imbalance contributes to CHF progression and explores the impact of autonomic dysregulation on post-transplant outcomes. By synthesizing existing evidence, the review highlights ANS modulation as a key therapeutic target for improving cardiac function and patient prognosis in both clinical settings.

Key Words: Chronic heart failure; Autonomic nervous system; Heart transplantation; Sympathetic nervous system; Parasympathetic nervous system

Core Tip: Autonomic nervous system (ANS) imbalance—marked by sympathetic overactivity and parasympathetic withdrawal—drives chronic heart failure (CHF) progression through oxidative stress, fibrosis, and catecholamine toxicity. Neuromodulation therapies aim to restore ANS balance and improve outcomes. After heart transplantation, autonomic dysfunction from denervation increases the risk of arrhythmias and hemodynamic instability, underscoring the prognostic value of partial reinnervation. This minireview highlights ANS modulation as a vital therapeutic target linking CHF management and post-transplant care to optimize cardiac function and long-term survival.

INTRODUCTION

Chronic heart failure (CHF) represents a progressive clinical syndrome characterized by diminished cardiac output and disrupted neurohormonal regulation, constituting a major contributor to global disability and premature mortality. According to epidemiological analyses from the Global Burden of Disease initiative, over 64 million individuals globally are affected by heart failure, demonstrating a 0.6% rise in age-standardized prevalence rates within a three-year observation period[1]. These statistics highlight the demand for wide-ranging investigations into therapeutic interventions. Substantial clinical evidence demonstrates that dysautonomia functions as both an initiating factor and pathognomonic feature in the development of heart failure and lethal arrhythmic events[2]. The autonomic regulatory network is composed of sympathetic and parasympathetic divisions. They play a critical role in cardiovascular homeostasis. During CHF progression, this regulatory system becomes pathologically imbalanced. It shows excessive sympathetic activation together with diminished vagal responsiveness. Such dysregulation provokes sustained catecholaminergic hyperactivation. This neurohormonal surge initiates a cascade of cellular disturbances through β-adrenoceptor hyperstimulation, including pathological calcium accumulation, mitochondrial redox imbalance, and initiation of programmed cell death signals. These processes ultimately lead to cardiomyocyte necrosis, programmed apoptosis, and interstitial collagen deposition. In recent years, advancements in neural modulation technologies have developed CHF management strategies. Therapeutic innovations in this field encompass catheter-mediated renal denervation[3], ablation of the greater splanchnic nerve[4], vagus nerve stimulation[5], pulmonary artery denervation[6], and cardiac contractility modulation systems[7]. Moreover, emerging investigations have revealed that autonomic instability significantly influences post-transplant outcomes. And restoring autonomic balance is a critical factor of graft survival[8].

This minireview investigates the bidirectional interplay between autonomic regulation and myocardial performance in the pathophysiology of CHF, with a focus on summarizing and illustrating the underlying mechanisms through visual representations. Meanwhile, we have evaluated the consequences of neural dysregulation in cardiac transplantation. We highlight the therapeutic primacy of autonomic modulation in CHF management and its vital role in post-transplant functional optimization. Elucidation of neurocardiac interactions may catalyze the development of precision therapies in order to potentially transform clinical outcomes for both CHF populations and transplant recipients.

CHF

CHF is a clinical syndrome characterized by impaired ventricular function due to structural or functional cardiac abnormalities, with primary manifestations including dyspnea, fatigue, and fluid retention[9,10]. Globally, approximately 65 million adults are affected by CHF, with half presenting as heart failure with reduced ejection fraction and an associated annual mortality rate of 10%–20%[11]. Epidemiological data from the United States indicate a prevalence of around 2% among adults, with frequent comorbidity involving chronic kidney disease (15% prevalence), where bidirectional cardiorenal interactions exacerbate disease progression[12].

The etiology of CHF is multifactorial, with ischemic heart disease (45%), hypertension (10%–15%), dilated cardiomyopathy (30%), and valvular disease representing the predominant underlying causes[13]. Pathological mechanisms include direct myocardial injury (e.g., infarction, myocarditis) or hemodynamic overload (e.g., pressure or volume overload). Emerging evidence also implicates dyssynchronous ventricular activation due to right ventricular apical pacing as a contributor to cardiac dysfunction through impaired output and fibrotic remodeling[14].

At the molecular level, CHF progression is driven by maladaptive neurohumoral activation, particularly autonomic imbalance marked by excessive sympathetic tone and diminished parasympathetic activity[15]. Chronic β-adrenergic stimulation leads to receptor downregulation, disrupted calcium homeostasis, and mitochondrial dysfunction, further impairing myocardial performance[16]. Concurrent parasympathetic withdrawal reduces heart rate variability (HRV) and baroreflex sensitivity, both established prognostic indicators in CHF[17]. Neuroimmune interactions further amplify disease progression, as sympathetic neurotransmitters promote pro-inflammatory cytokine release [tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6)], while impaired cholinergic signaling exacerbates systemic inflammation and fibrosis[18,19].

Current therapeutic strategies emphasize pharmacologic modulation of neurohormonal pathways, including renin-angiotensin-aldosterone system (RAAS) inhibitors (ACEIs, ARBs, or ARNIs), β-blockers, and mineralocorticoid receptor antagonists to attenuate remodeling and improve outcomes[20]. For end-stage disease, heart transplantation remains the definitive treatment, demonstrating significant improvements in ejection fraction (55%–65% postoperatively) and autonomic function, as evidenced by HRV recovery[21]. However, limited donor availability necessitates alternative approaches such as left ventricular assist devices, though these may reintroduce autonomic dysregulation, highlighting the need for adjunct neuromodulator strategies[22].

AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system (ANS), comprising the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), exerts opposing regulatory effects on cardiac and vascular function.

The SNS originates in the thoracolumbar spinal cord (T1–L3). Here, preganglionic neurons synapse with postganglionic neurons in paravertebral or prevertebral ganglia. Acetylcholine (ACh) released at these synapses activates nicotinic receptors, while postganglionic neurons secrete norepinephrine (NE), which acts on α- and β-adrenergic receptors. In the cardiovascular system, β₁-adrenergic receptors in the sinoatrial node and myocardium mediate increased heart rate, contractility, and conduction velocity (chronotropy, inotropy, and dromotropy, respectively)[23]. NE binding to β₁-receptors in the sinoatrial node accelerates phase 4 depolarization via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, increasing heart rate. Ventricular β₁-receptor activation raises intracellular cAMP levels, enhancing L-type calcium channel activity and myocardial contractility[24]. Furthermore, NE promotes coordinated ventricular activation by facilitating atrioventricular nodal conduction. Basal sympathetic tone sustains systemic vascular resistance through low-frequency α₁-receptor stimulation, while stress-induced α₁-mediated vasoconstriction further elevates peripheral resistance. β₂-receptor-mediated vasodilation occurs in specific vascular beds but remains a secondary effect under most conditions[25,26].

In contrast, the PNS modulates cardiac function primarily via vagal efferents originating from the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV) in the brainstem[27]. NA-derived cholinergic signaling exerts dominant inhibitory control over heart rate through the release of ACh, while DMV pathways may influence ventricular function through non-chronotropic mechanisms. Adenylate cyclase activity is suppressed when ACh binds to myocardial M₂ muscarinic receptors, coupling to Gi/o proteins. The resulting decrease in cAMP reduces the pacemaker current (If), slowing spontaneous depolarization and producing negative chronotropic and dromotropic effects[28]. Additionally, ACh activation of the I_kACh current shortens atrial action potential duration and prolongs ventricular effective refractory period, counteracting sympathetic effects and reducing arrhythmic potential. These parasympathetic mechanisms contribute to electrical stability and conduction homogeneity in the heart[29]. Moreover, the PNS functions within a complex integrative framework involving central autonomic modulation, respiratory coupling, and interactions with sympathetic and metabolic pathways, necessitating multidimensional approaches to fully elucidate its cardiovascular influence[30].

ANS DYSFUNCTION IN CHF: MECHANISTIC INSIGHTS

Although traditionally considered a hemodynamic disorder, CHF is now recognized as a neurohormonal syndrome involving dysregulation of the RAAS and ANS. A hallmark of CHF is autonomic imbalance, characterized by sustained sympathetic overactivity and reduced parasympathetic tone. This section explores the relationship between autonomic dysfunction and cardiac pathophysiology, with emphasis on mechanisms through which sympathetic dominance drives disease progression.

Excess sympathetic activity is a central contributor to CHF pathogenesis. Declining myocardial performance and peripheral hypoperfusion activate compensatory sympathetic responses, initially enhancing cardiac contractility, heart rate, and diastolic relaxation via β-adrenergic receptor stimulation[31]. However, chronic stimulation promotes cardiomyocyte hypertrophy and apoptosis[32]. SNS hyperactivity correlates with heart failure risk factors, may precede CHF onset, and is associated with inflammatory mediators[33]. Moreover, neurohormonal activity is influenced by comorbid conditions and genetic predisposition[34]. Mechanisms underlying sympathetic overactivation are discussed below.

Baroreflex dysregulation in CHF: A disrupted brake on sympathetic drive

Baroreflex dysfunction is an early contributor to SNS hyperactivity. CHF patients exhibit reduced baroreflex sensitivity, characterized by diminished inhibitory reflexes (e.g., arterial baroreceptor-mediated suppression of SNS) and enhanced excitatory reflexes (e.g., peripheral chemoreceptor activation)[35]. Consequently, the failing heart elicits exaggerated sympathetic responses to cardiopulmonary pressures. Baroreflex activation therapy (BAT) has emerged as a promising intervention, with meta-analyses demonstrating improved exercise capacity and symptom relief in patients with reduced ejection fraction[36].

Neurotrophic remodeling and cardiac sensitization: Nerve growth factor -driven sympathetic amplification

In advanced CHF, compensatory sympathetic overdrive triggers maladaptive remodeling. Altered cardiac nerve growth factor (NGF) levels regulate post-injury neuronal repair and sympathetic sprouting[37]. At the cardiac level, NGF modulates sympathetic innervation density, neuronal survival, and synaptic transmission between neurons and cardiomyocytes[38]. Experimental NGF infusion into the left stellate ganglion induces cardiac sympathetic hyperinnervation, increasing ventricular arrhythmia and sudden cardiac death (SCD) risks[39]. Thus, sympathetic sprouting may perpetuate SNS hyperactivity.

Neurochemical and humoral imbalances: Amplifiers of sustained sympathetic activation

CHF involves significant neurochemical remodeling of the SNS, notably in neurotransmitter dynamics and receptor responsiveness. Catecholamines (CAs), especially NE, activate myocardial β-adrenergic receptors, with NE levels in CHF patients reported up to 20 times higher than in healthy individuals. Chronic sympathetic stimulation impairs NE reuptake, sustaining elevated synaptic NE and prolonged adrenergic activation. This contributes to cardiotoxicity through interstitial fibrosis, myocyte hypertrophy, oxidative stress, and β-receptor desensitization/downregulation, ultimately diminishing inotropic reserve and accelerating disease progression[40].

Beyond intrinsic neurotransmitter alterations, systemic factors further amplify SNS activity. Circulating mediators such as vasopressin, glutamate, endothelin, angiotensin II (Ang II), TNF-α, and IL-6 enhance sympathetic outflow[41]. Ang II, a key RAAS effector, inhibits NE reuptake, perpetuating adrenergic drive[42], while inhibitory pathways—including neuronal nitric oxide synthase and gamma-aminobutyric acid ergic signaling—are suppressed, removing central restraint on sympathetic tone[43]. Together, these excitatory-inhibitory imbalances sustain sympathetic overactivation in CHF.

In parallel with sympathetic overactivity, PNS suppression also plays a critical role in the pathophysiology of CHF. Under normal physiological conditions, PNS activation counterbalances sympathetic tone, enhances baroreflex sensitivity, improves nitric oxide bioavailability, modulates RAAS activity, and regulates inflammatory cytokine release[44]. However, in CHF, diminished vagal activity disrupts this regulatory equilibrium, thereby facilitating sustained sympathetic dominance and accelerating disease progression. Emerging therapeutic strategies aimed at augmenting parasympathetic tone—such as vagal nerve stimulation—have shown promise in restoring autonomic balance and alleviating heart failure severity by targeting multiple pathophysiological pathways simultaneously. Figure 1 provides a visual summary of the following mechanisms.

Figure 1 This infographic illustrates the pathological mechanisms of chronic heart failure. It shows multiple disrupted physiological processes. Reduced regulation of inflammatory cytokines, decreased nitric oxide production, and attenuation of the renin-angiotensin-aldosterone system ameliorative effects impact cardiac and renal functions. Impaired baroreflex sensitivity involves altered arterial baroreflex and chemoreceptor reflex. Cardiac and central sympathetic sensitization is evident, with cardiac sympathetic nerve sprouting and neurotransmitter/receptor alterations, like sustained high norepinephrine levels. The balance between the parasympathetic and sympathetic nervous systems is disrupted. Also, changes in environmental chemical mediators occur, such as increased alcohol dehydrogenase, glutamate, endothelin, angiotensin II, tumor necrosis factor-α, interleukin-6 and decreased nitric oxide synthase and gamma-aminobutyric acid, etc. These factors collectively contribute to the complex pathophysiology of chronic heart failure, highlighting the systemic and multifactorial nature of the disease. RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system; PNS: Parasympathetic nervous system; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; LSG: Left stellate ganglion; NFG: Nerve growth factor; NE: Norepinephrine; GABA: Gamma-aminobutyric acid; nNOS: Neuronal nitric oxide synthase; Ang II: Angiotensin II.

ANS IN CHF HEART TRANSPLANTATION

ANS dynamically regulates cardiac function through sympathetic and parasympathetic (vagal) pathways. Previous studies have demonstrated that sympathetic activation accelerates heart rate and elevates blood pressure, whereas vagal excitation decelerates cardiac rhythm and reduces blood pressure. However, in transplanted hearts, the complete surgical transection of neural connections leads to an initial state of denervation, followed by a partial reinnervation process during postoperative recovery.

Preoperative phase: Autonomic dysregulation in end-stage heart failure

End-stage heart failure exhibits sympathovagal imbalance characterized by sympathetic hyperactivity and vagal suppression. Diminished baroreceptor responsiveness secondary to reduced cardiac output and hypotension perpetuates neurohormonal activation. Chronic β1-adrenergic stimulation induces cardiomyocyte receptor downregulation, causing CAs desensitization despite pathologically elevated NE (≥ 600 pg/mL). Excess CAs exacerbate cardiovascular pathophysiology via α1-mediated vasoconstriction, β1-driven myocardial hypercontractility, oxidative tissue injury, and calcium dysregulation-induced arrhythmogenesis. Targeted preoperative CAs modulation in transplant candidates may mitigate sympathetic overdrive and potentially improve post-transplant outcomes. Heart failure progression induces parasympathetic suppression, manifested through reduced vagal tone, HRV depletion (standard deviation of normal-to-normal intervals (SDNN) < 70 ms, low-frequency/high-frequency ratio < 0.5), and diminished ventricular fibrillation threshold-collectively elevating arrhythmogenic susceptibility. Preoperative HRV quantification provides prognostic stratification of autonomic impairment, mandating β-blockade to restore autonomic equilibrium and enhance arrhythmic thresholds[45].

Intraoperative phase: Pharmacological management of surgically denervated allografts

The intraoperative complete surgical transection of neural connections between the donor heart and recipient results in ablation of central autonomic regulation, rendering the transplanted heart dependent on humoral CAs (epinephrine, NE) and local autocrine/paracrine factors for functional modulation. Subsequent to denervation, the allograft loses baroreflex-mediated compensatory capacity to hemodynamic perturbations, necessitating continuous infusion of vasoactive agents (e.g., dopamine 2-10 μg/kg/minute, NE 0.05-0.3 μg/kg/minute) to maintain end-organ perfusion pressure.

Postoperative phase: Impact of the ANS on cardiac recovery and disease prognosis

Relevant studies have shown that cardiac transplant recipients > 1 month post-surgery exhibit persistent tachycardia and impaired autonomic indices (reduced directional coupling, acceleration capacity, and HRV) compared to healthy controls. While SDNN demonstrates progressive elevation with prolonged survival duration, directional coupling and acceleration capacity remain static[46]. The denervated graft undergoes adaptive remodeling, relying on humoral rather than neural regulation. Vagal denervation causes resting tachycardia, and delayed epinephrine response blunts exercise-induced heart rate increases. Simultaneous epinephrine-mediated vasoactivity and preload-dependent stroke volume maintenance render blood pressure acutely sensitive to volume shifts, predisposing recipients to orthostatic hypertension[47]. Table 1 shows the difference between normal heart and transplanted heart[48,49].

Table 1 Comparation between normal heart and transplanted heart.

	Normal heart	Transplanted heart
Sinus rhythm	60-100 bpm	90-110 bpm[48]
Exercise-induced heart rate response	Rapid elevation	Delay[48]
Blood pressure regulation	Baroreflex-mediated rapid regulation	Dependent on humoral regulation and preload[49]
Heart rate variability	Normal	Chronically low[48]

In denervated hearts post-transplantation, the absence of afferent and efferent innervation eliminates nociceptive signaling, precluding typical angina. As a result, rejection often manifests as isolated diastolic dysfunction or silent ischemia, necessitating routine surveillance via serial endomyocardial biopsies and coronary angiography to detect microvascular injury and subclinical coronary disease. Autonomic modulation—pharmacological or via targeted neuromodulation—restores sympathovagal balance, lowering baseline heart rate, improving rate control, and attenuating hypertensive responses to volume shifts. This neurohumoral recalibration facilitates prodromal symptom recognition (e.g., exertional angina), enabling earlier intervention[50]. Preventive strategies targeting endothelial dysfunction, oxidative stress, and inflammation mitigate long-term acute myocardial infarction and coronary atherosclerotic heart disease risk. Partial sympathetic reinnervation, observed in about 50% of recipients within 1–3 years via 123I-MIBG scintigraphy, enhances chronotropic responses through restored β-adrenergic sensitivity and CAs contractility[51]. However, sympathetic reinnervation often shows marked spatial and temporal heterogeneity, leading to asymmetric or incomplete neural recovery across the heart. This imbalance significantly affects cardiac electrophysiology, increasing repolarization dispersion, refractoriness heterogeneity, and regional autonomic tone disturbances, such as localized sympathetic hyperactivity. These changes create a pro-arrhythmic substrate that heightens the risk of severe ventricular arrhythmias and SCD, particularly in patients with prior myocardial injury. Therefore, assessing the symmetry and completeness of sympathetic reinnervation is crucial for risk stratification and prevention of fatal arrhythmias. Vagal reinnervation remains limited, as indicated by persistently reduced HRV (e.g., SDNN, root mean square of successive differences) and baroreflex impairment. Although partial autonomic recovery reduces postoperative complications, asymmetric reinnervation may induce ventricular arrhythmias due to electrophysiologic heterogeneity, warranting extended ECG monitoring[52]. Ultimately, reestablishing autonomic balance stabilizes sinus rhythm, improves exertional heart rate adaptation, reduces preload-dependent strain, and lowers hypertensive and ischemic risk through suppression of neurohormonal overactivity and improved coronary perfusion.

CONCLUSION

The pathophysiology of CHF is fundamentally linked to ANS dysregulation, characterized by sympathetic hyperactivity and parasympathetic suppression. This neurohormonal imbalance drives disease progression through CAs-mediated myocardial toxicity, fibrotic remodeling, oxidative stress, and impaired cardioprotective signaling, establishing a self-perpetuating cycle of cardiac deterioration. In cardiac transplantation, denervation-induced autonomic dysfunction predisposes recipients to arrhythmogenesis and vascular maladaptation, underscoring the prognostic implications of ANS recovery. Restoring autonomic equilibrium emerges as a critical therapeutic target for both CHF management and post-transplant care. Multidisciplinary integration of mechanistic research, clinical innovation, and precision medicine strategies may optimize ANS modulation, potentially enhancing functional outcomes and long-term survival in these patient populations. Further research should explore strategies to enhance parasympathetic reinnervation post-transplant and validate neuromodulation therapies in large-scale clinical trials.